TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis.
Animals
Behavior, Animal
Cell Movement
/ genetics
Centrosome
/ metabolism
Cerebral Cortex
/ abnormalities
Disease Models, Animal
Embryo, Mammalian
Epilepsy
/ genetics
Female
Fibroblasts
/ cytology
Gene Knock-In Techniques
Genetic Predisposition to Disease
HeLa Cells
Humans
Intravital Microscopy
Male
Malformations of Cortical Development
/ genetics
Mice
Mice, Transgenic
Microscopy, Confocal
Microscopy, Electron
Microtubules
/ genetics
Mutation, Missense
Neurogenesis
/ genetics
Neurons
/ physiology
Tubulin
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 05 2019
13 05 2019
Historique:
received:
15
05
2018
accepted:
05
04
2019
entrez:
16
5
2019
pubmed:
16
5
2019
medline:
14
6
2019
Statut:
epublish
Résumé
De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1
Identifiants
pubmed: 31086189
doi: 10.1038/s41467-019-10081-8
pii: 10.1038/s41467-019-10081-8
pmc: PMC6513894
doi:
Substances chimiques
TUBG1 protein, human
0
TUBG1 protein, mouse
0
Tubulin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
2129Références
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